Radioactive capsules



Unite St res re sifii iii 3,159,545 RADHQAQTHVE QAPSULES Ralph EdwardKidwell and Edward Robert Laiton, Wauhcgan, EL, assignors to AhhottLaboratories, North Chicage, ill., a corporation of iiiinois No Drawing.Filed (lot. t, 196%, Set. No. 6%,312 '7 Claims. till. l67--83) Thisinvention relates to radioactive capsules and particularly to capsuleswherein radioactive compounds are retained without leakage.

The use of various radioactive substances in medicine is continuouslyextending, and such widespread use accordingly requires additional meansby which said radioactive substances can be administered. In clinicalmedicine, it is often desirable to administer a radioactive compoundorally for both diagnostic and therapeutic purposes. Since the handlingof radioactive substances presents serious contamination problems,extraordinary precautions must be taken in the handling andadministration thereof. One such successful method employs a dry layerof radioactive material adsorbed on the inside surface of a gelatincapsule such as is described in US. 2,911,338. The method and practicedisclosed in this patent are operable for the many radioactive compoundswhich can be dissolved in an organic volatile solvent. However,compounds which are not soluble in such solvents or are present inanother basically dilferent physical form (an oil) are not particularlyadaptable to be deposited as a dry layer within a gelatin capsule.

An oil such as glycerol trioleate has been tagged with a radioactivematerial and has been used as a tool in the study of fat metabolism.This radioactive isotope has been commonly deposited within a capsuleand has been scaled therein by the simple step of telescoping a topcapsule portion over a bottom portion of reduced diameter wherein iscontained the radioactive oil. This particular embodiment has seriousdisadvantages in that the oil can possibly leak from the containedcapsule, thereby causing serious contamination and reduction of theradioactive energy content. The possibility of such leakage is presentand likely in ordinary handling, but the disadvantage is compounded manytimes by the necessary presence of air freight transport. Someradioactive isotopes used in clinical medicine have relatively shorthalf lives and, consequently, time becomes the all-important factor inpreparing and handling such capsules. The rapid delivery by airplanecargo shipment is a necessary factor in establishing the procedureswhich will secure the greatest economy of time. The use of the airplaneto ship capsules containing radioactive substances in the liquid form,despite other advantages, aggravates the leakage problem because of thedecreased air pressure at higher elevations. While passenger cabins arepressurized, it is seldom, if ever, that storage compartments for airfreight cargoes are pressurized. It has been the unfortunate experienceof persons concerned with. this art that such capsules with theircontained radioactive liquids are received in a crushed or collapsedstate rendering such capsules useless and a radiation hazard.

It is an object of this invention to provide capsule forms ofradioactive compounds.

it is another object of this invention to provide a capsule in whichradioactive compounds in the liquid form can be incorporated andretained.

It is still another object of this invention to provide capsule formswhich will not leak a radioactive compound originally presented in aliquid form.

A still further object of this invention is to provide ca sules suitablefor oral administration wherein a liquid form of a radioactive compoundis incorporated in a waxlike vehicle.

In the accomplishment of the foregoing objects and other objects whichwill be apparent, it is now provided that a radioactive compound isplaced in a capsule with a vehicle which is a solid at below bodytemperatures (37 C.) and melts at higher temperatures. It has now beenfound that radioactive compounds can be incorporated in those vehiclescommonly employed in the suppository art. Such combined vehicle andradioactive compound can then be placed in a capsule suitable for oralingestion and retained therein as a solid state below body temperatures.This novel article of manufacture significantly decreases anycontamination hazard and eliminates the leakage of the radioactivecompound from within the capsule. The radioactive compound is mixed witha suitable wax and oil of proper proportions so that the resultingmixture is a solid at temperatures lower than 37 C., but melts attemperatures at or above this level.

The novel pharmaceutical form is prepared by melting a suitable wax andoil, combining therein the desired radioactive compound, transferringthe molten mixture into a capsule, allowing the molten mixture to coolinto a solid form and, thereafter, encapsulating the capsule so that thesolid vehicle and radioactive compound therein is entirely containedwithin the capsular walls. The actual volume of molten mixture which istransferred to the capsule will be determined by the degree ofradioactivity desired in the final product which, in turn, is determinedby the amount of activity actually in the mixture 'on the day ofpreparation. Since radioactive decay constantly occurs, the procedureprescribes a preliminary assay of the molten mixture containing theradioactive source and thereafter selecting an appropriate volume ofsaid mixture in order to provide a particular range of activity in thecapsule on the day of preparation. Reference to standard decay curvesfor the particular radioactive source incorporated will enable thepractitioner to prepare capsules which will contain a desired activityat some ascertained future date of use.

Such capsules can be handled with greater assurance of freedom fromradioactive contamination and can be quickly transported by air or othermeans without the extraordinary handling precautions which werenecessary prior hereto in order to guard against leakage. Airtransportation is now an added advantage because the lower temperaturesof air flight make the wax-like vehicle harder, therefore, providinggreater resistance to the damaged effects of lowered pressure. The greatadvantages obtained in the handling of such capsules are worthwhilebecause the pharmaceutical form is beneficially absorbed and utilized bythe human. The attending clinician administers such a capsule to thepatient and once the capsule reaches the stomach of the patient, thecapsule material is disintegrated, the solid vehicle melts and theradioactive compound is absorbed.

The capsules comprising an element disclosed herein are composed of anon-toxic, therapeutic, water-soluble material such as gelatin, methylcellulose, polyvinyl alcohol or other thermoplastic, water-soluble,non-toxic materials which are therapeutically acceptable. The vehiclefor the radioactive compounds is basically composed of a solid waxgenerally having melting points materially in excess of 37 C. and asolid oil which is of a lower melting point, but when mixed with theforegoing waxes in proper proportions results in a solid form whichmelts 1 larger amount of solid oil which melts at a lower level in orderto obtain the resultant solid form at temperatures lower than 37 C. Thechoice of the waxes and solid oils is within the ordinary skill of theman in the art, once he is apprised of the teachings of this invention.

The skilled practitioner will first select solid oils and Waxes whichare non-toxic and compatible with the human organism. He will nextcompound the oil and wax in the proper proportion to obtain a solidhaving the melting characteristics described herein. Representative anduseful oils are theobroma oil (cocoa butter), hydrogenated or partiallyhydrogenated vegetable and plant oils such as corn, palm kernel,cottonseed, peanut, saffiower, olive and other operable solid oils.Suitable waxes are carbowax, spermaceti, glycerol monostearate, beeswax,cetyl alcohol and other suitable low or highmelting, non-toxic,pharmaceutical waxes.

It is a purpose of this invention to provide a vehicle which melts atabout 37 C., but is a solid at lower temperatures. The amount of solidoil and wax which must be combined to obtain a solid melting at about 37C. is determined by the allegation method. The allegation method isWidely known and practiced among skilled pharmacists; it is representedby the following schematic formula:

ALLEGATION M.P Parts oil c x 37 1 011 Q 37z wax wax y J r) parts Theabove schematic formula states that an oil of known melting point and awax of known melting point can be combined to prepare a solid melting at37 C. by as many parts of the oil as are equal to the ditferenceof themelting point between the wax and 37 C.; and as many parts of the wax asare equal to the difference of the melting point of the wax and 37 C.Thus, with, for example, theobroma oil melting at 33 C. and spermacetimel ing at 46 C., the parts required to make a solid melting at 37 C.would be determined by the following allegation.

theobroma oil 33 C.

Parts 9 theobroma oil 4 spermaceti 13 total parts spermaccti Theprinciples of allegation are also applicable in the event more than twoingredients are intended for combination. An example would be thecombination of two solid oils of differing melting points with a solidwax of still another melting point. Recourse may be made to standardpharmaceutical texts in order to ascertain the method for combining suchmixtures into a final composition melting at about 37 C.

The radioactive compounds suitable for incorporation in the combinationof the present invention are those compounds which have a known useafter oral administration to the human. Such uses may either bediagnostic or therapeutic. Radioactive compounds which have beenadministered orally to the human for numerous purposes are radioactiveiodine, glycerol trioleate, oleic acid, triiodothyronine and others. Theradioisotopes which have a particular utility and which are prescribedorally can be determined by current recourse to the state of thisdynamic art, for the new compounds which are tagged with radioactiveatoms are constantly increasing in number and in application. If aparticular radioisotope has been described in the art as an orallyuseful agent, then such compound can be incorporated in the novelcombination disclosed herein.

The radioactive forms which are particularly useful for the presentembodiment are those which occur as oils,

such as glycerol trioleate and oleic acid. These comall pounds areliquid oils and, therefore, are particularly adaptable to beingincorporated directly in the oil-wax combination which comprises thesolid vehicle. The foregoing oils have unsaturated bonds in their chainswhich are suitably tagged with radioactive iodine Other oils with doublebonds can also be tagged with such radioactive isotopes, e.g., corn oil,sai'llower oil and the like.

Unsaturated oils tagged at their double bonds will not become solidifiedoils. It is to be remembered that only a minute number of oil moleculesare tagged with iodine an any given operable volume of oil. A specificactivity of about 1-2 millicuries per ml. of oil is sufficient to meetmost diagnostic and therapeutic requirements, but such activitycorresponds to a saturation of very few double bonds in a 1 ml. volumeof said oil.

The foregoing oils tagged with radioactive iodine can be combined inequal volumes with the solid oil-wax combination which has beencompounded to melt at 37 C. as set out hereinbefore. The combination ofan equal volume of oil with the solid vehicle compounded to melt at 37C. does not significantly alter such melting point. For radioactivesubstances which occur naturally as oils, another inert oil can beemployed as a diluent such as peanut oil or other vegetable oils. It ispreferred to use an equal volume of the oil alone or diluted withanother oil, which is to be combined with the solid vehicle because suchvolumes are easy to handle, easy to calculate and do not alter themelting point of the final composition. If the amount of oil added tothe vehicle base is substantially greater than an equal volume, theresulting mixture tends not to form a firm solid melting in the desiredrange. Therefore, it is a preferred and well-advised practice toincorporate at least an equal volume of the vehicle base to the oil. Ofcourse, lesser volumes of the oil will not significantly affect thedesired melting point range even though the mass tends to become morefirm.

it should be understood that radioactive materials which are not oilscan also be incorporated in the wax-like vehicle to obtain similaradvantages from the invention. Such radioactive substances can be eithera dry powder form which carries the radioactive compounds or suspensionsand emulsions thereof.

Dry crystalline and powder forms can be incorporated directly into thewax-like vehicle by a mixing step. A prepared vehicle base which meltsat substantially 37 C., as illustrated hcreinbefore, is melted orsoftened by heat, and the dry radioactive form is placed therein andmixed. It is apparent that incorporating such dry forms into the presentembodiments attains advantages in the subsequent handling andadministration of the radioactive materials. Hazards of contaminationfrom capsular leakage or damage are virtually eliminated while,concurrently, an elegant pharmaceutical form for oral administration isprovided.

It is also intended that suspensions and emulsions of radioactivecarriers can be incorporated into the embodiments of the presentinvention. A practitioner may desire to employ suspensions rather thanplacing a waterinsoiuble material directly into the vehicle base asdescribed hereinbefore. Such suspensions can be prepared by conformingwith the conventional procedures provided by that art and, thereafter,mixing said suspensions with the melted vehicle base.

The following examples are presented to illustrate the preparation ofthe novel capsule combinations, but it should be understood that suchexamples are meant to be representative and illustrative withoutimplying any limitations which are not warranted by the disclosurepresented herein.

Example I Ingredient: Amount Theobroma oil 4.753 gms. 8 1 Spermaceti2.334 gms.

Glycerol triole'ate, 1 tagged (1-2 mc./ml.)

The theobroma oil and spermaceti are melted on a steam bath attemperatures not exceeding 75 C. The glycerol trioleate is added to thismixture and thoroughly mixed. The combined volume of the theobroma andspermaceti is 8 ml. which results in a vehicle melting at about 37 C.When this vehicle is combined with the equal volume of 1 tagged glyceroltrioleate, the melting point of the final composition is not alteredfrom 37 C. A volume of approximately 0.2 ml. of this melted mixture isremoved by a pipette and transferred into a bottom half of a gelatincapsule while taking the conventional precautions against radiationhazards. The upper half of the gelatin capsule is telescoped over thebottom portion and the melted mixture within the capsule is allowed tosolidify. The foregoing formulation provides a sufiicient amount ofmelted material to prepare about 80 gelatin capsules. The solidifiedmixture melts in the range of 3436 C. Each capsule contains an activityof about 50-100 ,uc. as calibrated to a future date of use orapproximately 120 ,uC. of 1 activity as of day of preparation.

Example II Ingredient: Amount Glycerol monostearate 4 parts 1 Theobromaoil parts Glycerol trioleate, 1 tagged 4 ml.

The procedure steps outlined in Example I are followed to prepare 40gelatin capsules wherein each capsule contains an activity of about50-100 [10. as calibrated to a future date of use.

Example III Ingredient: Amount Theobroma oil 4.753 gms.} 1 Spermaceti2.334 gms.

Oleic acid, 1 tagged (l-2 mc./m1.) 8 ml.

The theobroma and spermaceti are melted and combined with the oleic acidby process steps as described in Example I. The combined melted mixtureis placed in a syringe which is aflixed to a syringe microburet, ModelSE22, manufactured by the Micro-metric Instrument Co. of Cleveland,Ohio. A heating tape, attached to a rheostat temperature control, iswrapped around the syringe to keep the waxes and oils in a molten state.The syringe microburet has a manually motivated plunger arm whichterminates at a position flush against the plunger arm of the syringe. Adial is connected to the plunger systems whereby the desired volume ofexpelled molten solids can be determined. Volumes of approximately 0.2ml. of expelled into each of the bottom portions of the gelatincapsules. The opening of the top portion of the gelatin capsule isdipped in an alcoholic solution of polyvinylpyrrolidone and thentelescoped over the bottom portion of the capsule containing the meltedcomposition. The alcoholic solution of polyvinylpyrrolidone serves toseal the capsule portions. The foregoing formulation provides asuflicient amount of melted mate- 6 rial to prepare about gelatincapsules. The solidified mixture melts in the range of 3234 C. Eachcapsule contains an activity of about 50-100 ,uC. as calibrated to afuture date of use.

()thers may practice the invention in any of the numerous ways whichwill be suggested by this disclosure to one skilled in the art. All suchpractice of the invention is considered to be a part hereof provided itfalls Within the scope of the appended claims.

We claim:

1. An article of manufacture comprising a pharmaceutical capsule formedof a non-toxic, water-soluble, thermoplastic material and a radioactivecomposition compounded from pharmaceutical oils and waxes within saidcapsule, said radioactive composition being a liquid at about 37 C. andremaining a solid at lower temperatures.

2. An article of manufacture comprising a pharmaceutical capsule formedof a non-toxic, Water-soluble thermoplastic material containing thereina radioactive composition compounded from pharmaceutical oils and waxes,said composition containing a radioactive material that is liquid, saidradioactive composition melting at about normal body temperatures andremaining substantially a solid at lower temperatures.

3. An article of manufacture according to claim 2 wherein thecomposition melting at body temperature is mixed with no more than anequal volume of Oil labeled with radioisotopes.

4. An article of manufacture :according to claim 2 wherein the capsuleis made of gelatin and the radioactive composition is compounded fromtheobroma oil and spermaceti wax.

5. An article of manufacture according to claim 2 wherein said capsuleis formed of gelatin and said radioactive composition is compounded fromtheobroma oil, spermaccti wax and glyceryl trioleate.

6. An article of manufacture according to claim 2 wherein said capsuleis essentially composed of gelatin and said composition comprisestheobroma oil, spermaceti wax and radioactive oleic acid.

7. An article of manufacture according to claim 2 wherein said capsuleis formed of gelatin and said composition is compounded from theobromaoil and spermaceti wax, and the radioactive material is introducedtherein as an oil.

References flited in the file of this patent UNITED STATES PATENTS2,780,355 Palermo et a1. Feb. 5, 1957 2,830,010 Valentine et al Apr. 8,1958 2,911,338 Tabern et al. Nov. 3, 1959 2,956,926 Greif Oct. 18, 19602,969,331 Brynko et a1 "Jan. 24, 1961 2,973,301 Klotz Feb. 28, 1961OTHER REFERENCES J.A.P.A., Sci. Ed., volume 39, No. 11, November 1950,pages 607-609.

1. AN ARTICLE OF MANUFACTURING COMPRISING A PHARMACEUTICAL CAPSULEFORMED OF A NON-TOXIC, WATER-SOLUBLE THERMOPLASTIC MATERIAL AND ARADIOACTIVE COMPOSITION COMPOUNDED FROM PHARMACEUTICAL OILS AND WAXESWITHIN SAID CAPSULE, SAID RADIOACTIVE COMPOSITION BEING A LIQUID ATABOUT 37*C. AND REMAINING A SOLID AT LOWER TEMPERATURES.